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1.
Am J Hematol ; 98(1): 102-111, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36260658

RESUMO

HCT recipients reportedly have a high mortality rate after developing COVID-19. SARS-CoV-2 vaccination is generally useful to prevent COVID-19. However, its safety and efficacy among HCT recipients remain elusive. This large-scale prospective observational study including 543 HCT recipients with 37-months interval from transplant demonstrated high safety profiles of mRNA vaccine: only 0.9% of patients avoided the second dose due to adverse event or GVHD aggravation following the first dose. Regarding the efficacy, serological response with a clinically relevant titer (≥250 BAU/mL) was obtained in 397 (73.1%) patients. We classified the remaining 146 patients as impaired responders and compared the clinical and immunological parameters between two groups. In allogeneic HCT recipients, multivariable analysis revealed the risk factors for impaired serological response as follows: age (≥60, 1 points), HLA-mismatched donor (1 points), use of systemic steroids (1 points), absolute lymphocyte counts (<1000/µL, 1 points), absolute B-cell counts (<100/µL, 1 points), and serum IgG level (<500 mg/dL, 2 points). Notably, the incidence of impaired serological response increased along with the risk scores: patients with 0, 1-3, and 4-7 points were 3.9%, 21.8%, and 74.6%, respectively. In autologous HCT recipients, a shorter interval from transplant to vaccination was the only risk factor for impaired serological response. Our findings indicate that two doses of SARS-CoV-2 vaccine are safe but insufficient for a part of HCT recipients with higher risk scores. To improve this situation, we should consider additional treatment options, including booster vaccination and prophylactic neutralizing antibodies during the SARS-CoV-2 pandemic.


Assuntos
COVID-19 , Transplante de Células-Tronco Hematopoéticas , Humanos , Anticorpos Antivirais , Formação de Anticorpos , COVID-19/prevenção & controle , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/efeitos adversos , População do Leste Asiático , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , RNA Mensageiro , SARS-CoV-2 , Transplantados , Vacinação , Japão
2.
Rinsho Ketsueki ; 64(6): 533-546, 2023.
Artigo em Japonês | MEDLINE | ID: mdl-37407479

RESUMO

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has improved survival for patients with hematological malignancy, especially for those highly at risk of relapse. However, disease relapse after allo-HSCT remains the most common cause of treatment failure and death, even with conventional chemotherapy and donor lymphocyte infusion. Disease relapse in allo-HSCT can be reduced via pre-emptive treatment based on measurable residual disease and maintenance therapy for patients at high risk of relapse as promising treatment strategies. Recently, the development of novel agents and cellular therapies with high antitumor activity and less toxicity, which can be used in the post-transplant setting, has increased their clinical applications in the therapeutic approach. This review examines the current landscape and future strategies for maintenance therapy, mainly for AML and ALL after allo-HSCT.


Assuntos
Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Recidiva Local de Neoplasia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/patologia , Estudos Retrospectivos
3.
Ther Drug Monit ; 44(4): 592-596, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35149666

RESUMO

BACKGROUND: Gilteritinib, a novel oral tyrosine kinase inhibitor, is used to treat acute myeloid leukemia (AML) with FMS-like tyrosine kinase-3 (FLT3) mutations. Therapeutic drug monitoring (TDM) of gilteritinib is important for improving clinical outcomes and ensuring safety. Therefore, this study aimed to develop a simplified method for quantifying gilteritinib in human plasma using liquid chromatography-tandem mass spectrometry. METHODS: Liquid chromatography was performed by using an Acquity BEH C18 column (50 mm × 2.1 mm, 1.7 µm) and a gradient elution with 0.1% formic acid in water (A) and acetonitrile (B). Detection was performed by using a Shimadzu tandem mass spectrometer through multiple reaction monitoring in the positive-ion mode. RESULTS: The developed method enabled quantification of gilteritinib in 4 minutes and was validated by evaluating selectivity, calibration curve (10-1000 ng/mL, r 2 > 0.99), a lower limit of quantification (LLOQ), accuracy (overall bias -4.2% to 1.9%), precision (intraday CV ≤ 7.9%; interday CV ≤ 13.6%), carryover, recovery, matrix effect, dilution integrity, and stability according to the US Food and Drug Administration (FDA) guidelines. This method was successfully applied to the TDM of gilteritinib trough concentrations in 3 patients with AML. CONCLUSIONS: The developed method fulfilled the FDA guideline criteria and can easily be implemented to facilitate TDM in patients receiving gilteritinib in a clinical setting.


Assuntos
Leucemia Mieloide Aguda , Espectrometria de Massas em Tandem , Compostos de Anilina , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Limite de Detecção , Mutação , Pirazinas , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/uso terapêutico
4.
Br J Haematol ; 194(1): 101-110, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33822354

RESUMO

Recently, the use of targeted synthetic or biological disease-modifying anti-rheumatic drugs (ts/bDMARDs) in addition to conventional synthetic (cs)DMARDs including methotrexate (MTX) for rheumatoid arthritis (RA) has increased. However, whether ts/bDMARDs are associated with the development and clinicopathological features of MTX-associated lymphoproliferative disorder (MTX-LPD) in patients with RA remains unknown. Therefore, we evaluated the clinical outcomes of 121 patients with MTX-LPD. Results showed that prior use of ts/bDMARDs was not associated with the different histopathological subtypes of MTX-LPD. Patients with polymorphic-type LPD had a better event-free survival than those with diffuse large B-cell lymphoma (DLBCL), classical Hodgkin lymphoma and peripheral T-cell lymphoma. The pathological subtype of lymphoma could predict the clinical outcome of MTX-LPD. In patients with DLBCL, the use of tumour necrosis factor-alpha (TNF-α) inhibitors prior to MTX-LPD onset was associated with a higher non-relapse mortality. Further, patients with RA previously treated with Janus kinase (JAK) inhibitors more commonly required chemotherapy than those treated with csDMARDs alone, indicating disease aggressiveness. Hence, special caution should be observed when managing patients with MTX-LPD previously treated with JAK or TNF-α inhibitors for RA.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Transtornos Linfoproliferativos/tratamento farmacológico , Metotrexato/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bleomicina/administração & dosagem , Ciclofosfamida/administração & dosagem , Dacarbazina/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Janus Quinases/antagonistas & inibidores , Estimativa de Kaplan-Meier , Linfoma não Hodgkin/mortalidade , Transtornos Linfoproliferativos/induzido quimicamente , Transtornos Linfoproliferativos/mortalidade , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Rituximab/administração & dosagem , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Vimblastina/administração & dosagem , Vincristina/administração & dosagem
5.
Ann Hematol ; 100(1): 197-208, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33150464

RESUMO

Retransplantation is the only curative treatment option for patients with acute lymphoblastic leukemia (ALL) that has relapsed after allogeneic hematopoietic cell transplantation (allo-HCT); however, data in this setting remain scant. Hence, this multicenter, retrospective study aims to determine outcome predictors after retransplantation in relapsed ALL. We examined 55 recipients who underwent multiple allo-HCTs during 2006-2018. The 2-year overall survival (OS), progression-free survival (PFS), and non-relapse mortality rates were 35.9%, 29.1%, and 23.6%, respectively. We observed a trend of better outcome in Ph + ALL (n = 22) patients compared with non-Ph ALL (n = 33) patients; the 2-year PFS was 40.9% versus 21.2%, indicating a beneficial effect of more potent second- or third-generation tyrosine kinase inhibitors. Univariate analysis revealed that late relapse after the previous transplant was the only significant predictor of better transplant outcome among Ph + ALL patients, whereas factors related to prolonged OS/PFS in non-Ph ALL patients were late relapse after the previous transplant, longer duration from disease relapse/progression to second or more allo-HCT, disease status at the transplantation, and good performance status. Nevertheless, further investigations are warranted to determine whether novel molecular-targeted agents with higher efficacy and fewer toxicities could exceed conventional chemotherapies as a bridging strategy to next allo-HCT and improve the outcomes of non-Ph ALL patients.


Assuntos
Transplante de Células-Tronco Hematopoéticas/tendências , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Condicionamento Pré-Transplante/tendências , Adolescente , Adulto , Idoso , Feminino , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , Retratamento/mortalidade , Retratamento/tendências , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Condicionamento Pré-Transplante/mortalidade , Resultado do Tratamento , Adulto Jovem
6.
Rinsho Ketsueki ; 62(8): 967-977, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497237

RESUMO

The etiology and pathogenesis of acute myeloid leukemia (AML) have been elucidated at chromosomal and genetic levels. The classification and prognosis for its treatment has clearly involved specific chromosomal aberrations and genetic mutations. The recent comprehensive genomic analysis represented by next-generation sequencers has led to discovering new genetic mutations in AML. These findings have not only been applied clinically as prognostic factors and MRD markers but also contributed to the development of new molecular-targeting drugs. Many new drugs have already been approved in the USA and Europe, and new stratified treatments have tried to incorporate them. With the advent of venetoclax, treatment strategies, especially for patients with poor prognosis and who are unfit, have been substantially revised, and the maintenance therapy for AML is also being reevaluated in accordance to the National Comprehensive Cancer Network guidelines. This article will review the current status of AML treatment in Japan and according to Western guidelines.


Assuntos
Leucemia Mieloide Aguda , Aberrações Cromossômicas , Genômica , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Prognóstico
7.
J Infect Chemother ; 26(5): 506-509, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32146107

RESUMO

Schizophyllum commune, a basidiomycete fungus, is a quite rare cause of invasive sinusitis for which no standard treatment has yet been established. We report herein a 59-year-old woman who developed S. commune rhinosinusitis after remission induction chemotherapy for her acute myeloid leukemia. No causative microorganisms were identified in the sinus lavage fluid culture, whereas nucleotide sequencing of the internal transcribed spacer region using endoscopic sinus biopsy specimen could confirm the pathogen as S. commune. Liposomal amphotericin B and voriconazole (VRCZ) treatment ameliorated both her clinical symptoms and laboratory findings. The patient was successfully treated with allogeneic stem cell transplantation, under continuous VRCZ administration, without aggravation of S. commune sinusitis. Molecular diagnosis and prompt intervention with suitable antifungal drugs may be crucial to manage this rare infectious complication.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Infecções Fúngicas Invasivas/complicações , Leucemia Mieloide Aguda/terapia , Rinite/microbiologia , Schizophyllum/patogenicidade , Sinusite/microbiologia , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Infecções Fúngicas Invasivas/diagnóstico , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/microbiologia , Leucemia Mieloide Aguda/complicações , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Rinite/complicações , Rinite/diagnóstico , Rinite/tratamento farmacológico , Schizophyllum/genética , Schizophyllum/isolamento & purificação , Sinusite/complicações , Sinusite/diagnóstico , Sinusite/tratamento farmacológico , Transplante Homólogo , Resultado do Tratamento , Voriconazol/uso terapêutico
8.
Ann Hematol ; 98(11): 2579-2591, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31628517

RESUMO

Umbilical cord blood transplantation (UCBT) is a curative treatment for hematological malignancies. However, appropriate prophylaxis against graft-versus-host disease (GVHD), aimed at obtaining rapid and stable engraftment and avoiding toxicity, remains controversial in UCBT. We retrospectively compared outcomes in 409 patients who received calcineurin inhibitors (CIs) plus conventional-dose methotrexate (conv-MTX/CIs, n = 77; methotrexate, 10 mg/m2 on day 1, 7 mg/m2 on days 3 and 6) with those who received CIs plus reduced-dose methotrexate (reduced-MTX/CIs, n = 209; methotrexate, 5 mg/m2 or 5 mg/body on days 1, 3, and 6) or CIs with mycophenolate mofetil (MMF/CIs, n = 123) for GVHD prophylaxis after UCBT. The cumulative incidence of neutrophil engraftment was significantly higher in the reduced-MTX/CI (82.3%) and MMF/CI (86.6%) groups than the conv-MTX/CI (71.4%) group (p = 0.014), although there were no differences in platelet recovery or infectious complications among the three groups. The incidence and severity of GVHD were comparable among the three groups, and there were no significant differences in transplantation-related mortality among the three groups. In conclusion, GVHD prophylaxis with reduced-dose methotrexate and MMF was closely associated with high incidence of neutrophil engraftment without an effect on the incidence and severity of GVHD, which was compared to GVHD prophylaxis with conventional-dose methotrexate.


Assuntos
Inibidores de Calcineurina/uso terapêutico , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Doença Enxerto-Hospedeiro/prevenção & controle , Imunossupressores/uso terapêutico , Metotrexato/uso terapêutico , Ácido Micofenólico/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores de Calcineurina/administração & dosagem , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/terapia , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Incidência , Infecções/epidemiologia , Infecções/etiologia , Japão/epidemiologia , Estimativa de Kaplan-Meier , Contagem de Leucócitos , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Neutrófilos , Contagem de Plaquetas , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
9.
Biol Blood Marrow Transplant ; 24(12): 2540-2548, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30026111

RESUMO

Human herpes virus-6 (HHV6)-associated myelitis and calcineurin inhibitor-induced pain syndrome (CIPS) are serious complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because these 2 complications cause similar sensory nerve-related symptoms, such as paresthesia, pruritus, and severe pain occurring around the engraftment, it can be difficult to differentially diagnose the 2 conditions. We retrospectively analyzed 435 recipients to distinguish clinical symptoms of these 2 complications. Twenty-four patients (5.5%) developed HHV6-associated encephalitis/myelitis; of these, 11 (2.5%) presented only with myelitis-related symptoms (HHV6-associated myelitis), which was confirmed by the detection of HHV6 DNA, and 8 (1.8%) had CIPS, with undetected HHV6 DNA. All patients with HHV6-associated myelitis or CIPS exhibited similar sensory nerve-related symptoms. Diagnostic images did not provide definite evidence specific for each disease. Symptoms of all patients with CIPS improved after switching to another immunosuppressant. Overall survival rate at 2 years for patients with HHV6-associated encephalitis/myelitis was significantly lower than that of CIPS (13.1% versus 29.2%; P = .049) or that of patients without HHV6-associated encephalitis/myelitis or CIPS (42.4%; P = .036), whereas there was no significant difference among the latter 2 groups (P = .889). The development of HHV6-associated encephalitis/myelitis but not CIPS was significantly associated with poor prognosis. Thus, transplant physicians should be aware that sensory nerve-related symptoms indicate early manifestations that might be correlated with reactivation of HHV6 or CIPS. Therefore, identification of HHV6 DNA is crucial for making a differential diagnosis and immediately starting appropriate treatments for each complication.


Assuntos
Inibidores de Calcineurina/efeitos adversos , Encefalite Viral/etiologia , Herpesvirus Humano 6/patogenicidade , Dor/induzido quimicamente , Transplante de Células-Tronco/efeitos adversos , Transplante Homólogo/efeitos adversos , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor/patologia , Adulto Jovem
10.
Biol Blood Marrow Transplant ; 24(11): 2302-2309, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29909153

RESUMO

Bloodstream infection (BSI) is a well-known cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Here, we conducted a retrospective study to assess the morbidity, etiology, risk factors, and outcomes of BSI in the postengraftment period (PE-BSI) after allo-HSCT. Forty-three of 316 patients (13.6%) developed 57 PE-BSI episodes, in which 62 pathogens were isolated: Gram-positive bacteria, gram-negative bacteria, and fungi, respectively, accounted for 54.8%, 35.5%, and 9.7% of the isolates. Multivariate analysis revealed methylprednisolone use for graft-versus-host disease (GVHD) prophylaxis (odds ratio [OR], 6.49; 95% confidence interval [CI], 1.49 to 28.2; P = .013) and acute gastrointestinal GVHD (GI-GVHD) (OR, 8.82; 95% CI, 3.99 to 19.5; P < .0001) as risk factors for developing PE-BSI. This finding suggested that GI-GVHD increases the risk of bacterial translocation and subsequent septicemia. Moreover, among patients with GI-GVHD, insufficient response to corticosteroids, presumably related to an intestinal dysbiosis, significantly correlated with this complication. Patients with PE-BSI presented worse outcome compared with those without (3-year overall survival, 47.0% versus 18.6%; P < .001). Close microbiologic monitoring for BSIs and minimizing intestinal dysbiosis may be crucial to break the vicious cycle between GI-GVHD and bacteremia and to improve transplant outcomes especially in patients who require additional immunosuppressants.


Assuntos
Bacteriemia/etiologia , Trato Gastrointestinal/patologia , Doença Enxerto-Hospedeiro/complicações , Transplante de Células-Tronco Hematopoéticas/métodos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/métodos , Adolescente , Adulto , Idoso , Bacteriemia/patologia , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
11.
Biol Pharm Bull ; 41(11): 1667-1671, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30381666

RESUMO

Chemotherapy-induced nausea and vomiting (CINV) are generally evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE). The Multinational Association for Supportive Care in Cancer (MASCC) developed the MASCC Antiemesis Tool (MAT) to facilitate recognition for CINV between patients and oncology specialists. In the present study, MAT and CTCAE were comparatively assessed in Japanese patients with hematological malignancies. A total of 61 patients were eligible for this study. The CTCAE data were collected from an electronic medical record system. The patients were asked to complete the Japanese version of MAT in the hospital, on the first and fourth days after the start of chemotherapy. The percentages of patients in whom nausea was completely controlled, with severity scores of zero, ranged from 70.5 to 82.0% for CTCAE and from 59.0 to 75.4% for MAT, during the first five days after the chemotherapy. The percentages of patients who had no vomiting ranged from 93.4 to 96.7% for CTCAE and from 90.2 to 98.4% for MAT. During the observation periods, the day-to-day response profiles of patients who received antiemetic treatment were comparable between CTCAE and MAT cohorts, and these two assessment tools showed good, positive correlations for nausea severity scores. The present study shows that the MAT is a useful tool for assessing the severity of CINV in patients with hematological malignancy, is comparable to CTCAE, and facilitates the identification of poor cancer care conditions by medical staff.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias Hematológicas/tratamento farmacológico , Náusea/induzido quimicamente , Índice de Gravidade de Doença , Inquéritos e Questionários , Vômito/induzido quimicamente , Adulto , Idoso , Antieméticos/uso terapêutico , Feminino , Hospitais , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Náusea/prevenção & controle , Vômito/prevenção & controle , Adulto Jovem
12.
Cancer Sci ; 108(8): 1628-1633, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28556364

RESUMO

The hedgehog signaling pathway regulates multiple morphogenetic processes during embryogenesis. Aberrant activation of the hedgehog pathway signal transduction in adult tissues is associated with the pathogenesis of hematologic malignancies and solid tumors. We report findings from an open-label, multicenter phase I trial of the selective, small-molecule hedgehog signaling inhibitor glasdegib (PF-04449913) in Japanese patients with select advanced hematologic malignancies. Glasdegib was administered as once-daily oral doses (25, 50 and 100 mg) in 28-day cycles after a lead-in dose on Day -5. The primary objectives were to determine first-cycle dose-limiting toxicities, safety, vital signs and laboratory test abnormalities. Secondary objectives included evaluation of pharmacokinetics, pharmacodynamics and preliminary evidence of clinical activity of glasdegib. No dose-limiting toxicities were noted in the 13 patients in the present study. All patients experienced at least one treatment-emergent, all-causality adverse event. The most frequent treatment-related adverse events (observed in ≥3 patients) were dysgeusia (n = 9), muscle spasms (n = 5), alopecia, decreased appetite (n = 4 each), and increased blood creatinine phosphokinase, constipation and diarrhea (n = 3 each). Two deaths occurred during the study and were deemed not to be treatment-related due to disease progression. Glasdegib demonstrated dose-proportional pharmacokinetics, marked downregulation of the glioma-associated transcriptional regulator GLI1 expression in normal skin, and evidence of preliminary clinical activity, although data are limited. Glasdegib was safe and well tolerated across the dose levels tested. It is confirmed that the 100-mg dose is safe and tolerable in Japanese patients, and this dose level will be examined in the future clinical trial.


Assuntos
Antineoplásicos/administração & dosagem , Benzimidazóis/administração & dosagem , Neoplasias Hematológicas/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Proteína GLI1 em Dedos de Zinco/genética , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hematológicas/genética , Humanos , Japão , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacologia , Resultado do Tratamento
14.
Biol Blood Marrow Transplant ; 22(9): 1608-1614, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27220263

RESUMO

Mogamulizumab (MOG), a humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, has recently played an important role in the treatment of adult T cell leukemia/lymphoma (ATLL). Because CCR4 is expressed on normal regulatory T cells as well as on ATLL cells, MOG may accelerate graft-versus-host disease (GVHD) by eradicating regulatory T cells in patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there is limited information about its safety and efficacy in patients treated with MOG before allo-HSCT. In the present study, 25 patients with ATLL were treated with MOG before allo-HSCT, after which 18 patients (72%) achieved remission. The overall survival and progression-free survival at 1 year post-transplantation were 20.2% (95% CI, 6.0% to 40.3%) and 15.0% (95% CI, 4.3% to 32.0%), respectively. The cumulative incidence of acute GVHD was 64.0% (95% CI, 40.7% to 80.1%) for grade II-IV and 34.7% (95% CI, 15.8% to 54.4%) for grade III-IV. The cumulative incidence of transplantation-related mortality (TRM) was 49.0% (95% CI, 27.0% to 67.8%). Six of 7 patients with acute GVHD grade III-IV died from GVHD, which was the leading cause of death. In particular, a shorter interval from the last administration of MOG to allo-HSCT was associated with more severe GVHD. MOG use before allo-HSCT may decrease the ATLL burden; however, it is associated with an increase in TRM due to severe GVHD. Because MOG is a potent anti-ATLL agent, new treatment protocols should be developed to integrate MOG at suitable doses and timing of administration to minimize unwanted GVHD development.


Assuntos
Anticorpos Monoclonais Humanizados/toxicidade , Doença Enxerto-Hospedeiro/induzido quimicamente , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia-Linfoma de Células T do Adulto/complicações , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Doença Aguda , Adulto , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Leucemia-Linfoma de Células T do Adulto/mortalidade , Leucemia-Linfoma de Células T do Adulto/terapia , Masculino , Pessoa de Meia-Idade , Indução de Remissão/métodos , Estudos Retrospectivos , Análise de Sobrevida , Transplante Homólogo
16.
Ann Hematol ; 94(7): 1159-65, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25704584

RESUMO

The introduction of reduced-intensity conditioning (RIC) regimens has made possible allogeneic hematopoietic cell transplantation (allo-HCT) in older patients with acute myeloid leukemia (AML). However, the optimal timing of allo-HCT in these patients and its relative risks and benefits when compared with chemotherapies have not been determined. This retrospective study by the Fukuoka Blood and Marrow Transplant Group compared RIC allo-HSCT with non-transplant therapies, the choice based on donor availability, in AML patients in their first complete remission (CR1). The prognostic value of various patient characteristics and disease-specific variables were investigated in 299 patients aged ≥60 years with AML in CR1. Among the 107 patients aged 60-65 years, 54 of whom received allo-HCT and 53 of whom continued chemotherapies; allo-HCT, adverse-risk group, and hematopoietic cell transplantation-comorbidity index were significant predictors of survival outcomes. Among 192 patients aged ≥66 years deemed ineligible for allo-HCT, relapse and Karnofsky performance status after induction therapy were significant predictors of survival outcomes. Findings from this study may facilitate a new standard of care for older AML patients in CR1 who are considered candidates for allo-HCT.


Assuntos
Análise Citogenética/métodos , Definição da Elegibilidade/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Idoso , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão/métodos , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendências , Transplante Homólogo/efeitos adversos , Transplante Homólogo/métodos
17.
Blood ; 120(19): 4058-67, 2012 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-22990013

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is characterized by deregulated engulfment of hematopoietic stem cells (HSCs) by BM macrophages, which are activated presumably by systemic inflammatory hypercytokinemia. In the present study, we show that the pathogenesis of HLH involves impairment of the antiphagocytic system operated by an interaction between surface CD47 and signal regulatory protein α (SIRPA). In HLH patients, changes in expression levels and HLH-specific polymorphism of SIRPA were not found. In contrast, the expression of surface CD47 was down-regulated specifically in HSCs in association with exacerbation of HLH, but not in healthy subjects. The number of BM HSCs in HLH patients was reduced to approximately 20% of that of healthy controls and macrophages from normal donors aggressively engulfed HSCs purified from HLH patients, but not those from healthy controls in vitro. Furthermore, in response to inflammatory cytokines, normal HSCs, but not progenitors or mature blood cells, down-regulated CD47 sufficiently to be engulfed by macrophages. The expression of prophagocytic calreticulin was kept suppressed at the HSC stage in both HLH patients and healthy controls, even in the presence of inflammatory cytokines. These data suggest that the CD47-SIRPA antiphagocytic system plays a key role in the maintenance of HSCs and that its disruption by HSC-specific CD47 down-regulation might be critical for HLH development.


Assuntos
Antígeno CD47/metabolismo , Citofagocitose/imunologia , Regulação para Baixo , Células-Tronco Hematopoéticas/metabolismo , Linfo-Histiocitose Hemofagocítica/etiologia , ADP-Ribosil Ciclase 1/metabolismo , Adolescente , Adulto , Idoso , Antígenos CD34/metabolismo , Antígenos de Diferenciação/genética , Antígeno CD47/genética , Linhagem Celular , Citocinas/farmacologia , Regulação para Baixo/efeitos dos fármacos , Humanos , Mediadores da Inflamação/farmacologia , Ativação de Macrófagos/imunologia , Macrófagos/metabolismo , Pessoa de Meia-Idade , Modelos Biológicos , Mutação , Interferência de RNA , Receptores Imunológicos/genética , Adulto Jovem
18.
Blood Cell Ther ; 7(2): 49-55, 2024 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-38854399

RESUMO

Infection is a major contributor to non-relapse mortality in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Detecting infectious diseases in febrile patients during pretransplant conditioning is crucial for subsequent transplant success. Procalcitonin (PCT) is an auxiliary diagnostic marker of severe bacterial infections and has been proposed as a useful predictor of infection in patients undergoing allo-HSCT. Pre-transplant use of anti-thymocyte globulin (ATG) can cause side effects, such as fever and hypotension, which must be distinguished from infectious diseases. Although ATG administration may increase PCT levels, data on PCT levels in febrile patients after ATG administration are limited. Furthermore, no studies have compared PCT levels during allo-HSCT conditioning using ATG or non-ATG regimens. To investigate whether ATG increases PCT levels during febrile episodes in pre-transplant conditioning and whether PCT could be used to discriminate infections during this period, we analyzed 17 ATG and 59 non-ATG patients with fever and who underwent PCT level measurements during pre-transplant conditioning. Our findings revealed that ATG administration was the only significant factor that increased PCT positivity during fever (p = 0.01). In contrast, infectious diseases did not affect PCT positivity in the ATG group (p = 0.24). Furthermore, bloodstream infection was a significant risk factor for PCT positivity in patients who received non-ATG regimens (p < 0.01). Incorporating PCT levels into the diagnostic workup for infectious diseases requires careful consideration, particularly for patients receiving ATG regimens.

19.
Bone Marrow Transplant ; 59(4): 466-472, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38238452

RESUMO

The "human leukocyte antigen (HLA) supertype" is a functional classification of HLA alleles, which was defined by structural features and peptide specificities, and has been reportedly associated with the clinical outcomes of viral infections and autoimmune diseases. Although the disparity in each HLA locus was reported to have no clinical significance in single-unit cord blood transplantation (sCBT), the clinical significance of the HLA supertype in sCBT remains unknown. Therefore, we retrospectively analyzed clinical data of 1603 patients who received sCBT in eight institutes in Japan between 2000 and 2017. Each HLA allele was categorized into 19 supertypes, and the prognostic effect of disparities was then assessed. An HLA-B supertype mismatch was identified as a poor prognostic factor (PFS: hazard ratio [HR] = 1.23, p = 0.00044) and was associated with a higher cumulative incidence (CI) of relapse (HR = 1.24, p = 0.013). However, an HLA-B supertype mismatch was not associated with the CI of acute and chronic graft-versus-host-disease. The multivariate analysis for relapse and PFS showed the significance of an HLA-B supertype mismatch independent of allelic mismatches, and other previously reported prognostic factors. HLA-B supertype-matched grafts should be selected in sCBT.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Doença Enxerto-Hospedeiro , Humanos , Prognóstico , Estudos Retrospectivos , Antígenos HLA , Antígenos de Histocompatibilidade , Antígenos HLA-B/genética , Recidiva , Alelos , Teste de Histocompatibilidade
20.
Int J Hematol ; 117(2): 287-292, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36136227

RESUMO

Donor-derived hematological malignancies have been recognized as rare but serious late complications in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Most cases in the literature were diagnosed as myelodysplastic syndrome or acute leukemia, with very few malignant lymphoma reported. We herein present another case of donor-derived Burkitt lymphoma that occurred 9 years after allo-HSCT under continued administration of immunosuppressants for chronic graft-versus-host disease (GVHD). The patient achieved a partial response after rituximab-combined intensive chemotherapy. To reduce the risk of relapse and to avoid organ toxicities due to repeated chemotherapies, we performed upfront high-dose chemotherapy followed by stem cell rescue using donor-derived CD34+ cells, called pseudo-autologous HSCT (pASCT), and adjusted immunosuppressants appropriately. The patient remained disease-free for 23 months after pASCT without exacerbation of cGVHD. Although the observation period has been relatively short and longer follow-up is needed, pASCT may be a feasible option for donor-derived lymphoma even in patients with active cGVHD.


Assuntos
Linfoma de Burkitt , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Linfoma , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante Autólogo , Linfoma de Burkitt/etiologia , Linfoma de Burkitt/terapia , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/patologia , Transplante Homólogo/efeitos adversos , Linfoma/complicações , Imunossupressores , Leucemia Mieloide Aguda/complicações
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